Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 https://doi.org/10.1186/s12958-018-0366-6

REVIEW Open Access Role of hormonal and inflammatory alterations in obesity-related reproductive dysfunction at the level of the hypothalamic-pituitary-ovarian axis Michelle Goldsammler1, Zaher Merhi2,3 and Erkan Buyuk1*

Abstract Background: Besides being a risk factor for multiple metabolic disorders, obesity could affect female reproduction. While increased adiposity is associated with hormonal changes that could disrupt the function of the hypothalamus and the pituitary, compelling data suggest that obesity-related hormonal and inflammatory changes could directly impact ovarian function. Objective: To review the available data related to the mechanisms by which obesity, and its associated hormonal and inflammatory changes, could affect the female reproductive function with a focus on the hypothalamic-pituitary- ovarian (HPO) axis. Methods: PubMed database search for publications in English language until October 2017 pertaining to obesity and female reproductive function was performed. Results: The obesity-related changes in hormone levels, in particular , , ghrelin, and agouti-related , are associated with reproductive dysfunction at both the hypothalamic-pituitary and the ovarian levels. The pro-inflammatory molecules advanced glycation end products (AGEs) and monocyte chemotactic protein-1 (MCP-1) are emerging as relatively new players in the pathophysiology of obesity-related ovarian dysfunction. Conclusion: There is an intricate crosstalk between the adipose tissue and the inflammatory system with the HPO axis function. Understanding the mechanisms behind this crosstalk could lead to potential therapies for the common obesity-related reproductive dysfunction. Keywords: Obesity, Ovary, HPO, Advanced glycation end products, Monocyte chemotactic protein-1

Background dyslipidemia, and cardiovascular disease [3]. Besides these According to a recent population study, approximately 39% chronic disorders, obesity is also associated with reproduct- of the population over the age of 20 and 18% of children ive and obstetric complications such as menstrual irregular- between the ages of 2–19 are obese [1]. Obesity causes a ities, subfertility, endometrial hyperplasia and cancer, as huge economic burden where it is estimated that obesity well as poor obstetrical and perinatal outcomes [4–7]. This will add 48–66 billion dollars in related health care expen- review will focus on the relationship between obesity and ditures by the year 2030 [2]. This is due to obesity-related female reproductive function with a focus on alterations in comorbidities such as diabetes mellitus, hypertension, the hypothalamic pituitary ovarian (HPO) axis and the dir- ect effect of obesity-related inflammatory processes on ovarian function.

* Correspondence: [email protected] 1 Montefiore’s Institute for Reproductive Medicine and Health, Department of Normal HPO Axis Obstetrics & Gynecology and Women’s Health, Albert Einstein College of Medicine, Montefiore Medical Center, Hartsdale, NY, USA The female reproductive physiology is a complex inter- Full list of author information is available at the end of the article action between neuroendocrine and endocrine signaling

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 2 of 10

affecting the hypothalamus, the pituitary gland and the fluctuations in peripheral steroid hormone secretion, ovaries. At the level of the hypothalamus, gonadotropin thereby impacting pubertal development [29]. For in- releasing hormone (GnRH) pulses activate the pituitary stance, the adipocytes contain aromatase, that both assists release of the two gonadotropins, follicle-stimulating in the production [30] and the conversion of steroid hor- hormone (FSH) and luteinizing hormone (LH) [8, 9]. mones, mainly androgens to . Population studies FSH and LH in turn act on the ovaries to stimulate fol- have demonstrated a trend for earlier menarche, due to licular growth and result in the production of the obesity epidemic, over the past 30 years [31], and, following ovulation, [10]. Estradiol, to- highlighting the potential for significant increase in health gether with ovarian inhibin B, acts primarily in a nega- care risks and cost for these young girls. Increased adipose tive feedback loop on the hypothalamus suppressing the tissue quantity rather than increased sensitization or in- release of FSH. When estradiol reaches a sustained creased aromatase activity during aging [32] and therefore threshold in concentration and duration, for at least 24– increased peripheral production of estrogens leads to in- 48 h [11–13], it provides a positive feedback that in- creased rate of serious hormone dependent cancers, such creases the frequency and decreases the amplitude of as endometrial and breast cancer [33, 34]. GnRH pulses thereby activating increased pituitary re- Obesity decreases pituitary LH pulse amplitude and lease of LH surge for ovulation to occur [14]. There are mean LH release without changing its frequency, leading multiple regulators of this cycle and our review is lim- to impaired luteal phase [35]. Additionally, obesity may ited to those regulators, which are altered, directly or in- affect various components of the HPO axis, and may directly, in overweight and obese women. have direct effect on ovarian function independent of The HPO axis plays a crucial role in pubertal transi- hypothalamic pituitary function. We will elucidate in the tion. Normal pubertal development is under two main following sections the changes that occur in the meta- controls, adrenal and hypothalamic [15]. The adrenal bolic and inflammatory systems that are related to ovar- glands participate in adrenarche, which often precedes ian dysfunction. the remainder of pubertal events. Adrenarche is inde- pendent of the hypothalamic pubertal changes as ob- Leptin served in several disorders of sexual differentiation [16]. Leptin is a 16-kDa adipokine secreted primarily by white The hypothalamus, with its GnRH pulse generator re- adipose tissue, although it can be secreted from other tis- sponsible for the initiation of puberty, is quiescent in sues, such as gastric mucosa [36]. Serum leptin levels posi- childhood, likely under GABAergic (gamma-aminobuty- tively correlate with the amount of adipose tissue in the ric acid) inhibitory control [17, 18]. Normal central acti- body [37]. Leptin has several functions, which in concert vation of the hypothalamus via and glutamate reflect body energy homeostasis. It acts to stimulate en- neurons in the arcuate nucleus results in nocturnal in- ergy expenditure and suppresses appetite via its signaling creases in low frequency LH pulses [19]. These pulses at the level of the hypothalamus [18, 38]. These findings become more prevalent throughout the day until the were confirmed with mouse knockout model where leptin GnRH pulse generator achieves the frequency and amp- knockout mice become obese with a rapid and litude sufficient for cyclic ovarian hormonal function persistent weight gain [39]. Because leptin suppresses ap- and ultimately menarche. During normal puberty, there petite, it was studied as a potential target for weight loss is a physiologic resistance that helps achieve the drug development [40]. However, it has been shown that anticipated pubertal weight gain and growth [20–22]. increased exogenous leptin does not necessarily induce The insulin resistance leads to decreased hepatic derived weight loss [41, 42] suggesting that there is a resistance circulating sex hormone-binding globulin (SHBG), state to the action of leptin at the level of the hypothal- which in turn increases circulating free estradiol levels. amus. Indeed, high circulating leptin levels observed in This may also contribute to a parallel adrenal activation obese women supports the concept of leptin resistance resulting in more androgen production and ultimately [37]. This desensitization to leptin is not a complete adrenarche [17, 18]. Increasing estradiol levels, in turn, blockage of leptin signaling and can possibly be reversed are significantly associated with growth velocity, [23] with weight loss [43]. possibly through the stimulation of the Leptin’s energy homeostatic function in part contrib- – Insulin like growth factor 1 (IGF-1) axis [24, 25]. utes to its effect on puberty. Puberty requires a certain energy balance to proceed [22, 44]. Leptin has a permis- Obesity and the HPO axis sive action for pubertal progression, but it is not the ini- It has been thought that obesity changes the expected tiator or the sole mechanism by which puberty occurs time course of puberty and leads to earlier thelarche, adre- [45]. Conversely, hyperleptinemia may initially cause narche and menarche [26–28]. Adiposity, and specifically earlier reproductive maturation, and prolonged high lep- the distribution of the adipose tissue, contributes to tin levels could lead to ovulatory dysfunction [46]. On Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 3 of 10

the other hand, low leptin levels observed in energy- intestinal peptides [63]. It is predominantly produced by deficient states are associated with delayed or lack of pu- the stomach, but is also detectable in many other tissues, berty, when puberty is not physiologically desired [47]. like bowel, pancreas, hypothalamus and pituitary [64]. Leptin affects GnRH pulse neurons indirectly though Ghrelin is increased in fasting states and stimulates ap- GABA or kisspeptin [39, 48]. Both GABA and kisspeptin petite to compensate for decreased nutritional intake neurons have a focus in the arcuate nucleus, where lep- [65]. Mouse models confirm that ghrelin increases food tin receptors are readily available [39, 49, 50]. Knockout consumption as an immediate and short-term effect [66] models for the that is found on GABA by acting on the arcuate nucleus in the hypothalamus specific neurons display delayed puberty and decreased and stimulates appetite via neuropeptide Y (NPY) and fecundability in animal models [39]. Similarly, loss of agouti related protein (AgRP) neurons [67]. One of ghre- function mutation in the kisspeptin gene results in lin’s targets is the hypothalamic arcuate nucleus where it delayed or absent puberty [51]. Hypothalamic kisspeptin increases the expression of NPY/AgRP mRNA [68] levels often correlate with leptin levels [50] in line with resulting in increased body weight and inhibiting proo- low energy states, making this an alternate pathway for piomelanocortin (POMC) neurons [69]. Double knock- leptin signaling [52]. Both low serum, and therefore out (NPY-/AgRP-) mouse models, or other NPY/AgRP hypothalamic, leptin levels and low hypothalamic kis- deficient models demonstrated suppression of ghrelin- speptin levels decrease LH secretion by the pituitary, ul- induced appetite stimulation as compared to wild type timately affecting ovulation [52]. control animals. Deficiency of both NPY and AgRP is Studies on the effect of leptin on ovarian folliculogenesis necessary to abolish the effect of ghrelin while knockout and ovulation have shown conflicting results. Leptin has of only one of these mediators is not sufficient to sup- been isolated in both mural and cumulus granulosa cells press ghrelin’s effect [66]. and within the follicular fluid of pre-ovulatory follicles in In the hypothalamus, ghrelin can decrease both GnRH women undergoing in vitro fertilization (IVF) [53]. Serum secretion and pulsatility [70–73] possibly through NPY- leptin levels increase after ovulation and have peak levels and AgRP- mediated mechanisms [74]. Vulliémoz et al. in the mid-secretory phase, possibly contributing to the suggested that this effect is part of the homeostatic control implantation window within the endometrium [54]. Some of reproductive function in response to nutritional studies suggested an inhibitory effect of leptin, especially changes. In low energy states, such as fasting, ghrelin on early follicular development, while others suggested levels are increased, thereby altering the HPO axis cyclic that leptin could induce ovulation, independent of LH activity [73]. Ghrelin also stimulates other pituitary hor- [55] since there seems to be an interaction between estra- mone release, such as adrenocorticotropic hormone and diol and leptin [55, 56]. In a mouse model, leptin adminis- [75]. In low energy states where ghrelin levels tration increased LH levels and follicular development are elevated, prolactin levels may be increased potentially corresponding to an increase in ovarian tissue weight [57]. leading to disruption of ovarian cyclicity. Ghrelin has not In addition, IVF outcome studies pointed to leptin as clearly been shown to have a direct effect on pubertal negatively correlated to reproductive outcome. In one transition. However, ghrelin levels decrease throughout study of serum leptin levels in patients undergoing IVF, childhood as puberty approaches [75]. Given its inverse higher leptin:BMI ratio was associated with a decreased relationship to adiposity, decreasing ghrelin levels may be number of good quality embryos and lower implantation a reflection of the increasing weight gain observed in the and pregnancy rates [58]. At the ovarian level [46], supra- pre-pubertal stage [76]. physiologic levels of leptin inhibits androstenedione and Studies on the effect of ghrelin on ovarian steroido- progesterone production [59, 60]. Additionally, human genesis have shown mixed results [74, 77]. Animal stud- granulosa and cumulus cells exposed to leptin in vitro lead ies suggest that ghrelin could induce estradiol and/or to a downregulation in anti-Müllerian hormone (AMH) progesterone production, [78] or could inhibit estradiol via the JAK/STAT pathway [61]poten- release via inhibiting CYP19A1 (aromatase enzyme) ex- tially leading to ovulatory dysfunction. In summary, nor- pression [74, 79, 80]. These effects may be dose- mal leptin homeostasis is required for normal physiologic dependent [81] or related to the activated portion of the functions at the level of the hypothalamus and the ovaries. ghrelin molecule [79]. The full-length ghrelin molecule While low levels of leptin could disrupt the GnRH pulsati- stimulates estradiol secretion while certain amino acid lity, supraphysiologic levels of leptin could disrupt ovarian fragments of ghrelin are inhibitory for estradiol secretion folliculogenesis [46, 55, 62]. [79]. Ghrelin could affect folliculogenesis by increasing cell proliferation and decreasing apoptosis and follicular Ghrelin atresia [82, 83 ]. Similarly, chronic ghrelin infusion leads to Ghrelin is an orexigenic enterokine composed of 28 increase in follicle number and decrease in corpus luteum amino acids related to the family of number in a rat model [84]. Additionally, ghrelin, with its Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 4 of 10

connection to obesity, is related to insulin regulation and with administration of exogenous adiponectin [102]. Low insulin resistance where it decreases insulin secretion and adiponectin levels, as seen in certain genetic polymor- sensitivity [64, 85, 86] ultimately leading to insulin resist- phisms, have been linked to insulin resistance, metabolic ance [87]. syndrome and type 2 diabetes mellitus [103–105]. Inter- Thus, these findings suggest that ghrelin may indir- estingly, the adiponectin gene is located at 3q27, near the ectly contribute to puberty through general energy diabetes susceptibility gene locus [103, 106]. Adiponectin homeostasis such as insulin action, and it acts at the is structurally similar to the pro-inflammatory TNF- α level of the hypothalamus, pituitary and ovary leading to family, however it functions as an anti-inflammatory adi- alterations in normal reproductive function. pokine, inhibiting the production of TNF-α within the adi- pocyte [102]. Conversely, pro-inflammatory agents such Neuropeptide Y and Agouti-related protein: (NPY/AgRP) as TNF-α, IL-6 and IL-8 are implicated in the develop- The connection between peripherally circulating adipo- ment of insulin resistance via hypothalamic inflammation kines, enterokines and the HPO axis centers on a collec- [107]. This inflammation in turn contributes to both insu- tion of neurons within the arcuate nucleus, which lin and leptin resistance, promoting further obesity and secrete the neuropeptides NPY and AgRP [88]. NPY is a subsequently diabetes [107]. In fact, in obese women adi- 36 amino acid neurotransmitter peptide predominantly ponectin levels are low and pro-inflammatory markers, expressed in sympathetic neurons. It stimulates fat such as TNF-α, IL-6, and CRP are increased [46]. angiogenesis and proliferation via both a central hypo- Adiponectin and its receptors are found in many or- thalamic and peripheral mechanism [49, 89]. AgRP is a gans including the ovaries [108–111]. Adiponectin acts 112 amino acid neuropeptide expressed in the arcuate in concert with insulin and IGF-1 to mediate changes nucleus [90, 91] and stimulates appetite [91]. Both NPY within the granulosa cells during the periovulatory and AgRP are orexigenic neurons and interact with phase. Through IGF-1, it increases ovarian production ghrelin to promote appetite [66]. of estradiol and progesterone in rat ovaries [108] pos- Under normal physiologic conditions, NPY concentra- sibly by up-regulating StAR gene [109]. It also causes tion increases in the portal capillary blood during the vasodilation with the upregulation of VEGF and COX-2 ovulatory surge to potentiate the action of GnRH on pi- expression in the periovulatory ovary [109]. Adiponectin tuitary gonadotropin secretion [92, 93]. Similarly, AgRP knockout mice show ovarian dysfunction reflected by engages the GnRH pulse generator neurons within the fewer oocytes, more atretic follicles, prolonged diestrus hypothalamus and regulates gonadotropin release. Both cycles and decreased LH receptor activity [112]. In a NPY and AgRP have tonic inhibitory effects where they retrospective case-controlled analysis, adiponectin levels could be stimulated by ghrelin in order to decrease were higher in women who conceived after IVF and GnRH pulse frequency and amplitude [94]. Infusion of positively correlated with the number of oocytes re- NPY, independent of ghrelin, also decreases pituitary LH trieved, independent of BMI [113]. Similarly, while adi- secretion [95]. NPY could have a negative regulatory im- ponectin levels are low or minimal in human and mouse pact on ovarian folliculogenesis where it could have a granulosa cells, its presence enhances fertilization rates pro-apoptotic and an anti-proliferative effect [96]. NPY and embryo development [114, 115]. has been shown to have no effect on progesterone secre- These findings suggest that adiponectin is notable for tion [97], but it recently has been found to stimulate es- its action in mediating insulin sensitivity, with its recep- tradiol and testosterone secretion in catfish [98]. Data tors found at every level of the reproductive axis making pertaining to the direct effect of NPY and AgRP on ovar- it a great therapeutic target for ovulatory dysfunction. ian steroidogenesis and folliculogenesis are still limited and further studies are required. Insulin Insulin is a 51 amino acid protein synthesized in the beta Adiponectin islet cells of the pancreas. Its release is stimulated by Adiponectin is a 30-kDa adipokine secreted by the adipose glucose in the gastrointestinal tract from ingestion, as tissue [99]. Opposite to leptin, adiponectin levels increase well as various amino acids directly [116]. Insulin levels with starvation [99]. Adiponectin acts in the brain by rise and its sensitivity decreases with obesity [116]. Insu- binding to the 1 (AdipoR1) in the ar- lin resistance, in conjunction with obesity, impacts cuate nucleus. This binding leads to activation of AMPK reproduction. While not a direct adipokine, adipose tis- resulting in increased food intake and reduced energy ex- sue stimulates pancreatic beta islet cells to release insu- penditure [100]. Adiponectin production increases insulin lin. Hyperinsulinemia acts on the liver to cause a sensitivity and is inversely correlated with adiposity [101]. decrease in SHBG production [117]. This in turn leads Knockout studies demonstrated that the absence of adipo- to increased free circulating steroid hormone levels, such nectin causes severe insulin resistance that is reversible as estrogens and androgens. Insulin increases androgen Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 5 of 10

production by two independent pathways; first by up- associated with chronic inflammation such as rheuma- regulating CYP17A1 enzymes, which increase androgen toid arthritis [125]. In addition to elevated circulating in- production in both the adrenal gland and the ovary flammatory markers, such as TNF-α, IL-6, and CRP [118]. Second, insulin augments LH action on the ovary [46], obese women have elevated levels of circulating to increase androgen production and secretion [118, AGEs [126] and MCP-1 [127]. In animal studies, obese 119]. Insulin resistance is associated with higher leptin mice have higher MCP-1 levels, which correlate with in- levels [38]. As noted previously, higher circulating leptin sulin resistance [128]. levels lead to leptin resistance which in turn leads to The pro-inflammatory AGEs may be part of the link greater insulin resistance. between diet-induced obesity and inflammation, with Insulin acts on the pituitary to modulate the GnRH re- AGEs inducing MCP-1 gene expression [129] thus form- ceptor and increases LH secretion after GnRH stimula- ing the AGEs/MCP-1 axis. AGEs are highly reactive tion [120]. Insulin augments FSH activity by increasing molecules formed by non-enzymatic cross-linking of ovarian steroidogenesis and inducing LH responsiveness , lipids and nucleic acids with glucose [130, 131]. [121]. Hyperinsulinemia is consequently associated with They may be formed endogenously or exogenously elevated basal LH levels and hyperandrogenism [119]. ingested as part of diet or through smoking [132]. AGE Insulin alone does not have an effect on ovarian re- levels are elevated in chronic diseases such as type 2 sponse to gonadotropic hyperstimulation during IVF in Diabetes Mellitus, metabolic syndrome, cardiovascular women without underlying insulin resistance [122]. Ra- disease, and neurodegenerative disorders [133–135]. ther, the changes seen during IVF stimulation are due to AGEs have also been studied for their effect on insulin resistance [122]. Syndromic severe insulin resist- reproduction [135–137]. ance, as seen in some genetic disorders, is associated Kandaraki et al. has demonstrated in human immortal- with enlarged ovaries and hyperandrogenism independent ized granulosa cells (KGN cell line) that AGEs attenuate of gonadotropin levels. Elevated insulin levels over a long LH- and FSH-induced ERK signaling needed for cell period of time can lead to increased autophosphorylation proliferation and proper follicular growth [138], one pos- of its receptor, which can inactivate one of its downstream sible mechanism for AGE-induced ovulatory dysfunc- transducers, GSK3. This inactivation can lead to spindle tion. Similarly, AGEs interfere with glucose transport disruption within growing oocytes [123, 124]. Additionally within granulosa cells [136]. Our recent data have shown high insulin levels during oocyte development disrupt that high-AGE diet could induce ovulatory dysfunction chromatin remodeling within mouse oocytes, thereby con- in a mouse model, as reflected by prolonged diestrus tributing to poorer oocyte quality [123]. Mouse models phase (unpublished data). We have also shown that show that the pituitary is still sensitive to changes in insu- high-fat diet induced obesity leads to ovulatory dysfunc- lin levels despite peripheral insulin resistance and basal tion in mice, as demonstrated by fewer oocytes ovulated hyperinsulinemia [120]. following superovulation compared to mice on normal Disruption of insulin signaling in diet-induced obesity chow diet (controls) [139]. This ovarian dysfunction was improves reproductive cyclicity in mice, suggesting that not observed in MCP-1 knockout mice that became insulin represents a mediator for pituitary LH dysregula- obese following ingestion of a high-fat diet, suggesting tion in obesity [120]. Further study of insulin at the level that lack of MCP-1 may be protective against high-fat- of the ovary, specifically in knockout and obesity-induced ovarian dysfunction. Further sup- mice in theca cells, also demonstrates improved cyclic porting this hypothesis, we showed that elevated serum reproduction in mice, showing a coordinated effect of MCP-1 levels were associated with poorer outcome in insulin along the HPO axis to disrupt cyclicity but not women undergoing IVF [140], an effect that is pro- pubertal onset [118]. In summary, insulin’s action is nounced in women with already diminished ovarian re- known to be necessary for changes in food intake and serve. Additionally, AGE levels in follicular fluid were body weight. Its well-studied actions on the HPO axis negatively correlated with IVF outcome parameters: and its relationship to adipokines such as leptin and adi- fewer oocytes retrieved and fertilized, fewer embryos ponectin makes it a major player in female reproduction. and lower ongoing pregnancy rate [137]. Taken together, these observations suggest that obesity may have direct AGEs and MCP-1 deleterious effects on the ovaries partly through activa- Obesity is a state of chronic inflammation with macro- tion of inflammatory AGE/MCP-1 axis. phage infiltration into various tissues. Macrophage infil- tration into adipose tissue is directly correlated to both Relationship between obesity and assisted reproductive the degree of adiposity as well as chemokine/adipokine technology (ART) outcome production, such as MCP-1 [125]. The pattern of macro- Population studies on the clinical sequelae of obesity phage infiltration is similar to that found in disorders provide a connection between obesity and subfertility. Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 6 of 10

Several studies indicated that obesity is a risk factor for and may actually be in part due to ethnic variations in BMI ovulatory dysfunction [141–143]. For women who ovu- rather than difference in ethnicity itself [159, 161]. late regularly, obesity increases the time to conception; Obesity could disrupt endometrial receptivity leading for instance, a high waist- height ratio decreases fecund- to poorer implantation rates [158, 165, 166], arguably ity by 30% [144]. Van der Steeg et al. found that in ovu- due to endometrial inflammation. Inflammatory markers latory infertile women (who underwent fertility such as IL-6 and TNF-α have been implicated in lower evaluation but did not yet receive treatment), for every implantation rates [46]. Similar to macrophage infiltra- BMI unit over 29, there was a 5% decrease in the prob- tion in the adipose tissue [125], we have shown that ability of a conception [145]. This increased time to con- there is increased expression of macrophage markers in ception is not only in the infertile population. Even in the ovaries of obese mice following the ingestion of a obese fertile women there was an increased time to con- high-fat diet [167]. Moreover, mice given high-fat diet ception from 3 to 5 months [146]. Other population stud- ovulated fewer oocytes following superovulation, further ies have shown that 33% of obese women at age 23 did supporting the notion that obesity may have direct effect not conceive spontaneously when trying to conceive for on ovaries, independent of HPO axis. Clearly the data to 12 months [147]. This increases the number of couples date demonstrates that obesity affects ART outcome in meeting criteria for infertility and therefore for potential women undergoing IVF possibly via actions on all as- ART interventions [147]. Obesity could also impact ovar- pects: oocyte, embryo and endometrium. ian reserve markers. Studies have shown that obesity is negatively correlated with serum AMH [148, 149], FSH, Conclusion LH and inhibin B levels [150]. These markers provide With the uncurbed obesity epidemic, more reproductive- ’ ’ added support for a cliniciansanalysisofacouplesfertil- aged women will face metabolic and reproductive compli- ity potential and may guide treatment options [151]. cations. Body energy hemostasis is closely linked to repro- Obesity does not only affect spontaneous pregnancy ductive function through many hormones, adipokines, rates in fertile patients, but it also confers a risk for cytokines, and growth factors that act at the level of the poorer ART outcome. While earlier data could not dem- brain and the ovaries. Obesity is also a state of chronic in- onstrate adequate convincing evidence of poorer ART flammation, which may directly affect ovarian function outcome parameters, recent data supports this correl- possibly by increased macrophage infiltration in the ovar- ation. Large national cohort studies as well as systemic ies through MCP-1 mediated pathways. The elevation of reviews and meta-analyses suggest that increasing BMI AGEs in the serum and tissues of obese women may ex- is negatively correlated with implantation, clinical preg- acerbate the reproductive dysfunction associated with adi- – nancy, and live birth rates [152 154]. Obese patients re- posity and may provide, along with MCP-1, a crucial link quire higher doses of gonadotropins but achieve lower between obesity and ovarian macrophage infiltration. Each serum estradiol levels and lower number of oocytes re- of these molecules and their prospective pathways may trieved [152, 155]. The oocytes of obese women tend to represent potential therapeutic targets in order to improve be smaller with decreased fertilization potential, leading the overall reproductive health of overweight/obese to a decreased blastocyst formation and decreased women. Obesity, with its alterations in the AGEs/MCP-1 trophectoderm cell number [156]. Additionally, obese axis, could disrupt the ovarian microenvironment poten- women have higher cycle cancellation rates, possibly due tially compromising oocyte competence, formation of to changes in pharmacodynamics of GnRH antagonists healthy embryos and ultimately conception. (clinically used to inhibit ovulation) leading to early LH Finally, this review underscores a critical need to un- surge and premature ovulation [157]. While not all stud- cover the mechanistic actions of molecules that affect al- ies identified these specific adverse ART outcome mea- most every level of the HPO axis. Obesity, a significant sures (i.e. smaller oocytes, decreased embryo quantity and growing public health problem, is an overwhelming and quality), they still demonstrated a lower clinical condition that causes reproductive disturbances in women – pregnancy and live birth rates up to 50% decrease com- in part due to ovarian dysfunction. Losing weight is com- pared to control women with normal BMI [152, 158]. monly challenging and often not sustainable. Thus there is The poorer IVF outcomes observed in obese patients a need to establish therapies for ovarian dysfunction and are quite intriguing. These observations suggest that the to improve ovarian health in the obese patient population. effect of obesity on ovarian function is not solely dependent on the HPO axis, since gonadotropins are sup- Authors’ contributions plied exogenously during IVF cycles, thus bypassing All authors contributed to the collection of literature data and writing of the manuscript. All authors read and approved the final manuscript. the HPO axis. Obesity adversely impacts ART outcome dif- – ferently in different ethnic populations [159 161]. However, Ethics approval and consent to participate these findings were inconsistent in the literature [162–164] N/A Goldsammler et al. Reproductive Biology and Endocrinology (2018) 16:45 Page 7 of 10

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